Lookup NU author(s): Dr Carole Proctor,
Professor Doug Gray
Background: Recent evidence suggests that glycogen synthase kinase-3 beta (GSK3 beta) is implicated in both sporadic and familial forms of Alzheimer's disease. The transcription factor, p53 also plays a role and has been linked to an increase in tau hyperphosphorylation although the effect is indirect. There is also evidence that GSK3 beta and p53 interact and that the activity of both proteins is increased as a result of this interaction. Under normal cellular conditions, p53 is kept at low levels by Mdm2 but when cells are stressed, p53 is stabilised and may then interact with GSK3 beta. We propose that this interaction has an important contribution to cellular outcomes and to test this hypothesis we developed a stochastic simulation model. Results: The model predicts that high levels of DNA damage leads to increased activity of p53 and GSK3 beta and low levels of aggregation but if DNA damage is repaired, the aggregates are eventually cleared. The model also shows that over long periods of time, aggregates may start to form due to stochastic events leading to increased levels of ROS and damaged DNA. This is followed by increased activity of p53 and GSK3 beta and a vicious cycle ensues. Conclusions: Since p53 and GSK3 beta are both involved in the apoptotic pathway, and GSK3 beta overactivity leads to increased levels of plaques and tangles, our model might explain the link between protein aggregation and neuronal loss in neurodegeneration.
Author(s): Proctor CJ, Gray DA
Publication type: Article
Publication status: Published
Journal: Molecular Neurodegeneration
Print publication date: 26/01/2010
ISSN (electronic): 1750-1326
Publisher: BioMed Central Ltd.
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